Local delivery of water-soluble or water-insoluble therapeutic agents to the surface of body lumens

ABSTRACT

A method and device for local delivery of water-soluble or water-insoluble therapeutic agents to the tissue of a normal or diseased body lumen is disclosed. An expandable structure of a medical disposable device, such as a balloon of a balloon catheter, is coated with a non-durable coating which is complexed with iodine and has a substantially water-insoluble therapeutic agent dispersed therein. The medical disposable device is inserted into a body lumen, and expanded to contact the non-durable coating against the body lumen and deliver the substantially water-insoluble therapeutic agent to the body lumen tissue.

RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.12/712,134, filed Feb. 24, 2010 now U.S. Pat. No. 8,128,951, which is acontinuation-in-part of pending U.S. patent application Ser. No.12/558,420, filed Sep. 11, 2009, which is a continuation-in-partapplication of U.S. patent application Ser. No. 12/210,344, filed Sep.15, 2008 now U.S. Pat. No. 8,257,722, the full disclosures of which areincorporated herein by reference.

FIELD

Embodiments of the present invention relate to the field of medicaltherapeutic agent delivery. More particularly embodiments of thisinvention relate to methods and devices used for local delivery ofwater-soluble or water-insoluble therapeutic agents to the surface ofnormal or diseased body lumens.

BACKGROUND INFORMATION

Sporadic, inherited, environmental, and iatrogenic diseases associatedwith significant morbidity and mortality develop in the wall ofendothelial cell-lined and epithelial cell-lined body lumens. Forexample, atherosclerosis and post-procedural restenosis develop in thearterial wall. Adenocarcinoma, esophageal varices, andcholangiocarcinoma develop in the gastrointestinal tract wall. Theefficacy of systemic drug therapy for these diseases may be limited byinadequate drug delivery to the diseased tissue and/or dose limitingtoxic effects in non-diseased tissue. Local delivery of drugs todiseased tissue in body lumen walls can overcome these limitations:therapeutic concentrations of drugs can be achieved without systemictoxicity.

SUMMARY

Embodiments of the present invention disclose a novel approach tocoating an expandable structure of a medical disposable device, such asa balloon of a balloon catheter, which can be used for local therapeuticagent delivery to the surface of body lumens. The approach permitsforming a coating with high levels of a therapeutic agent (e.g.paclitaxel) and utilizes a unique chemical formulation designed topermit forming a coating that provides a uniform therapeutic agentdensity across the balloon surface using a simple, reproducible andhence easily manufacturable application process. This novel coatingprocess can be used to locally delivery a uniform dose of water-solubleand water-insoluble therapeutic agents to treat a variety of diseasesthat arise in body lumen walls. In addition, the novel coating approachmay accommodate therapeutic levels of combinations of therapeutic agents(e.g. paclitaxel and dexamethasone acetate) directed at distincttherapeutic targets to increase the therapeutic efficiency of theprocedure.

In an embodiment, a coating solution is single-dip coated on anexpandable structure having an outer surface, such as an angioplastyballoon useful for either coronary or peripheral arteries of thevasculature, in order to form an amphiphilic polymer coating on theouter surface of the expandable structure. The coating solution maycontain an amphiphilic polymer or co-polymer in majority or exclusivelynon-aqueous solvents, a therapeutic agent or combination of therapeuticagents (e.g. paclitaxel and dexamethasone acetate), and an optionalplasticizer and/or wax. In an embodiment, the amphiphilic polymer orco-polymer is complexed with iodine, which is not covalently bound tothe amphiphilic polymer or co-polymer. The coating solution may alsocontain a plurality of amphiphilic polymers or co-polymers. Aftercoating, the balloon is dried and folded for delivery.

The coated medical disposable device may be used in a therapeuticoperation. In an embodiment, the coated medical disposable device isinserted into a body lumen and expanded to contact the non-durableamphiphilic polymer coating against the body lumen. Hydration of thecoating occurs immediately when exposed to aqueous fluids, such as bloodin vivo, causing the non-durable amphiphilic polymer coating to dissolveand the therapeutic agent to release into tissue of the body lumen. Inan embodiment, the significant or total solubility of the amphiphilicpolymer or co-polymer in blood may prevent embolic hazards associatedwith the amphiphilic polymer coating, and allow for the coating to bequickly and uniformly removed from the medical disposable device duringthe therapeutic operation. Thus, the amphiphilic polymer coating isbioerodable in the sense that it is removable by bodily fluids, andnon-durable. In an embodiment, at least 50%, by volume, of theamphiphilic polymer coating is removed from the device within 180seconds of inflating in vivo. In an embodiment, at least 90% of theamphiphilic polymer coating is removed from the device within 300seconds of inflating in vivo, and more preferably within 90 seconds ofinflating in vivo. Also, this active dissolution of the amphiphilicpolymer coating may assist in the transfer of hydrophobic, substantiallywater-insoluble therapeutic agents such as paclitaxel from the device(e.g. balloon) to the tissue.

In accordance with embodiments of the invention, the amphiphilic polymeror co-polymer may be complexed with iodine. It is demonstrated thatcomplexed iodine increases the solubility of water-insoluble therapeuticagents such as paclitaxel, rapamycin and everolimus in aqueousconditions. This suggests that the complexed iodine may additionallyassist in tissue uptake of the water-insoluble therapeutic agents invivo. In an embodiment, the dried amphiphilic polymer coating includes atherapeutic agent dispersed in a polymer matrix comprising at least oneamphiphilic polymer or co-polymer complexed with iodine, an optionalplasticizer and/or wax.

The amphiphilic polymer or co-polymer can be fully or partiallyamphiphilic. In an embodiment, a continuous aggregate polymer matrix ofthe coating is uniformly dissolvable and removable from an outer surfaceof an expandable structure of a catheter assembly in an aqueous solvent,and at least partially dissolvable in a non-aqueous solvent. Beingsignificantly or fully dissolvable in aqueous solvents is advantageousin that total solubility in blood can prevent against embolic hazardsassociated with the amphiphilic polymer coating. Having at least partialsolubility in non-aqueous solvents is advantageous in a coating processin which an amphiphilic polymer or co-polymer and water-insolubletherapeutic agent are dissolved in the same solution.

In an embodiment, the dried amphiphilic polymer coating comprises atleast one amphiphilic polymer or co-polymer complexed with iodine and atleast one amphiphilic polymer or co-polymer which is not complexed withiodine. In an embodiment, 25-100 wt % of the total amphiphilic polymeror co-polymer in the dried coating is complexed with iodine. Forexample, the dried coating may contain 0-75 wt % of an amphiphilicpolymer which is not complexable with iodine and 25-100 wt % iodinatedPVP as amphiphilic polymer components.

In an embodiment, the dried coating present on the balloon has an iodineto iodine complexable amphiphilic polymer and/or co-polymer weight ratio(I/P) of 1-30%, a therapeutic agent (drug) to polymer matrix weightratio (D/P) from 25-100%, and a drug density of approximately 0.1-10.0μg/mm². In an embodiment, the dried coating is present on a catheterballoon, the drug is paclitaxel, and the amphiphilic polymer is PVP. Thedried coating has an iodine to PVP weight ratio (I/P) of 1-30%, apaclitaxel to polymer matrix weight ratio (D/P) from 25-100%, and apaclitaxel density of approximately 0.1-5.0 μg/mm².

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a side view illustration of a balloon catheter while theballoon is in the expanded position.

FIG. 1B is an isometric view illustration of a balloon catheter dippedin a coating solution while the balloon is in the expanded position.

FIG. 1C is a side view illustration of a balloon catheter with a coatedballoon surface.

FIG. 2A is a side view illustration of an amphiphilic polymer coatingdisposed on an outer surface of unexpanded balloon of a balloon cathetercovered by a retractable sheath and inserted into a body lumen.

FIG. 2B is a side view illustration of an amphiphilic polymer coatingdisposed on an outer surface of unexpanded balloon of a balloon catheteradjacent to the focal area of local therapeutic agent delivery within abody lumen.

FIG. 2C is a side view illustration of the interface of the amphiphilicpolymer coating disposed on an outer surface of an expanded balloon of aballoon catheter and the focal area of local therapeutic agent deliverywithin a body lumen.

DETAILED DESCRIPTION

Embodiments of the present invention disclose methods and devices usedfor local delivery of water-soluble or water-insoluble therapeuticagents to the surface of normal or diseased body lumens.

Various embodiments described herein are described with reference tofigures. However, certain embodiments may be practiced without one ormore of these specific details, or in combination with other knownmethods and configurations. In the following description, numerousspecific details are set forth, such as specific configurations,compositions, and processes, etc., in order to provide a thoroughunderstanding of the present invention. In other instances, well-knownprocesses and manufacturing techniques have not been described inparticular detail in order to not unnecessarily obscure the presentinvention. Reference throughout this specification to “one embodiment”or “an embodiment” means that a particular feature, configuration,composition, or characteristic described in connection with theembodiment is included in at least one embodiment of the invention.Thus, the appearances of the phrase “in one embodiment” or “anembodiment” in various places throughout this specification are notnecessarily referring to the same embodiment of the invention.Furthermore, the particular features, configurations, compositions, orcharacteristics may be combined in any suitable manner in one or moreembodiments.

In one aspect, embodiments of the invention disclose a medicaldisposable device in which an amphiphilic polymer coating is disposed onthe outer surface of an expandable structure. The amphiphilic polymercoating includes at least one therapeutic agent and at least oneamphiphilic polymer or co-polymer. The amphiphilic polymer coating mayoptionally include additional components such as a plasticizer and/orwax. The therapeutic agent can be either water-soluble orwater-insoluble. Hydration of the amphiphilic polymer coating occursimmediately when exposed to aqueous fluids such as blood in vivo causingthe amphiphilic polymer coating to dissolve and the therapeutic agent torelease into tissue of the body lumen. In an embodiment, the significantor total solubility of the polymer or co-polymer in blood prevents anyembolic hazard associated with the amphiphilic polymer coating, andallows for the coating to be quickly and uniformly removed from themedical disposable device during the therapeutic operation.

In an embodiment, the medical disposable device is a catheter with anexpandable balloon having an amphiphilic polymer coating comprising atherapeutic agent dispersed in the coating. The catheter is advancedwithin a body lumen to align the balloon with the target tissue, theballoon is expanded to 2-20 atmospheres to bring the amphiphilic polymercoating into contact with the target tissue, causing the amphiphilicpolymer coating to dissolve and the therapeutic agent payload to releaserapidly to the target tissue in vivo because the device will contact thetarget tissue for only a short amount of time, approximately 5 to 300seconds. Because the device is to be used for only a short time periodand then removed from the body, it is considered to be a “medicaldisposable” device rather than “implantable.”

The term amphiphilic as used herein means at least partially dissolvablein aqueous solvents such as, but not limited to, blood in-vivo, as wellas at least partially dissolvable in non-aqueous solvents such as, butnot limited to, ethanol, methanol, and/or isopropanol. Accordingly, an“amphiphilic polymer coating” and “amphiphilic polymer or co-polymer”according to embodiments of the invention are at least partiallydissolvable in both aqueous and non-aqueous solvents.

In some embodiments, the amphiphilic polymer or co-polymer is fullyamphiphilic, meaning fully dissolvable in both aqueous and non-aqueoussolvents. Being fully dissolvable in aqueous solvents is advantageous inthat total solubility in blood can prevent against embolic hazardsassociated with the amphiphilic polymer coating, and allow for thecoating to be quickly and uniformly removed from the medical disposabledevice during the therapeutic operation. Being fully dissolvable innon-aqueous solvents is advantageous in a coating process where anexpandable structure may be dip coated into a non-aqueous coatingsolution in which the amphiphilic polymer or co-polymer and awater-insoluble therapeutic agent are dissolved.

In some embodiments, the amphiphilic polymer or co-polymer is not fullyamphiphilic. For example, the amphiphilic polymer or co-polymer mayexhibit significant or total solubility in aqueous solvents in order toprevent against embolic hazards associated with the amphiphilic polymercoating, and allow for the coating to be quickly and uniformly removedfrom the medical disposable device during the therapeutic operation.Also, the amphiphilic polymer or co-polymer may exhibit only partialsolubility in non-aqueous solvents. In some instances, water may beadded to a coating solution in order to dissolve the amphiphilic polymeror co-polymer. For example, a coating solution may be prepared in whichthe amphiphilic polymer or co-polymer and a water-insoluble therapeuticagent are dissolved in a mixture of aqueous and non-aqueous solvents. Inan embodiment, the coating solution contains a majority of non-aqueoussolvents. In an embodiment, the coating solution contains a ratio in therange of 100% to 80% non-aqueous solvent, and 0% to 20% aqueous solvent.

In an embodiment, additional components are included in the amphiphilicpolymer coating that may not necessarily be dissolvable in both aqueousand non-aqueous solvents, yet the aggregate polymer matrix of theamphiphilic polymer coating is at least partially dissolvable in bothaqueous and non-aqueous solvents. For example, embodiments of theinvention may utilize water-soluble and/or water-insoluble therapeuticagents, as well as a water-insoluble wax or other componentsinterdispersed in the aggregate polymer matrix of the amphiphilicpolymer coating. In an embodiment, a minority weight percent of ahydrophobic polymer or co-polymer can be included in the polymer matrixof the amphiphilic polymer coating. For example, a small minority ofhydrophobic polymer or co-polymer could be added to extend the lifetimeof the coating in vivo or slightly retard the release rate of thetherapeutic agent, while still allowing rapid and uniform dissolution ofthe coating in vivo.

In an embodiment, an amphiphilic polymer coating may include asubstantially water-insoluble component dispersed within an amphiphilicpolymer or co-polymer which is significantly or fully dissolvable inaqueous solvents but not fully soluble in non-aqueous solvents. In suchan embodiment, the continuous aggregate polymer matrix of the coating isuniformly dissolvable and removable from a substrate in aqueous solvents(such as bovine serum, or blood in vivo), yet only partially dissolvableand removable from a substrate in non-aqueous solvents.

In an embodiment, an amphiphilic polymer coating may include asubstantially water-insoluble component dispersed within an amphiphilicpolymer or co-polymer which is fully dissolvable in both aqueous andnon-aqueous solvents. In such an embodiment, the continuous aggregatepolymer matrix of the coating is uniformly dissolvable and removablefrom a substrate in both aqueous solvents (such as bovine serum, orblood in vivo) and non-aqueous solvents. The particular solubility rateof the amphiphilic polymer coating may depend upon the particularsolubility rate of the amphiphilic polymer(s) and/or co-polymer(s), andthe inclusion of any additional ingredients such as plasticizers, waxes,hydrophobic polymers or co-polymers, etc. in the coating. In anembodiment, an amphiphilic polymer or co-polymer is selected which has asufficiently high solubility rate in aqueous solutions in order to beutilized in a touch and go procedure where the coating is exposed tobodily fluids for only a short amount of time. In an embodiment, anamphiphilic polymer or co-polymer is selected which can be dissolved ina non-aqueous coating solution or an aqueous/non-aqueous coatingsolution in which a water-insoluble therapeutic agent is also dissolved.

Amphiphilic Polymers or Co-Polymers

In one aspect, embodiments of the invention disclose an amphiphilicpolymer coating including one or more amphiphilic polymers orco-polymers. In an embodiment, the amphiphilic polymer or co-polymer isa non-ionic thermoplastic polymer or co-polymer. In an embodiment, theamphiphilic polymer is hydroxypropyl cellulose (HPC), polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), methyl cellulose,hydroxypropyl methylcellulose, or co-polymers of N-vinylpyrrolidone withother reactive double bond containing monomers such as styrene, acrylicacid, vinyl acetate or vinyl caprolactam. PVP and HPC exhibit highersolubility rates in aqueous solvents than PEG. Molecular weight of thepolymers may also factor into solubility rates. In an embodiment, thePEG has as molecular weight of 1.5 KD to 50 KD.

In an embodiment, the amphiphilic polymer or co-polymer is complexedwith iodine and the iodine is not covalently bonded to the amphiphilicpolymer or co-polymer. For example, PVP, PEG and HPC may be complexedwith iodine, and it is expected that other suitable polymers such asmethyl cellulose, hydroxypropyl methylcellulose, and co-polymers ofN-vinylpyrrolidone with other reactive double bond containing monomerssuch as styrene, acrylic acid, vinyl acetate or vinyl caprolactam mayalso be complexed with iodine. In an embodiment, the PEG complexed withiodine has as molecular weight of 1.5 KD to 50 KD. PVP complexed withiodine is also known as povidone iodine. Surprisingly, as suggested bythe results of Table I and Table II, complexing a non-ionic amphiphilicpolymer with iodine may increase solubility of a water-insolubletherapeutic agent such as paclitaxel, rapamycin and everolimus in vivoand therefore assist in tissue uptake of the water-insoluble therapeuticagent. This can reduce the time requirements of the medical procedureand amount of mechanical pressure and/or metabolic insufficienciescaused by sustained inflation of the expandable structure. In anembodiment, the amount of iodine complexed with the iodine complexableamphiphilic polymer and/or co-polymer in the coating is 1 to 30 weight %of the dry iodine complexable amphiphilic polymer and/or co-polymerweight.

In an embodiment, the dried coating comprises at least one amphiphilicpolymer or co-polymer complexed with iodine and at least one amphiphilicpolymer or co-polymer which is not complexed with iodine. In anembodiment, 25-100 wt % of the total amphiphilic polymer or co-polymersin the dried coating are complexed with iodine. For example, 25-100 wt %of the total amphiphilic polymer and/or co-polymer in the polymer matrixmay be povidone iodine.

Complexing with iodine can also serve addition functions. It imparts anamber hue on the amphiphilic polymer coating, aiding in visualizationoutside of the body, and with the coating process. Additionally, asiodine has a large nuclear radius, it will provide radiopacity underfluoroscopy; the expandable structure will be visible under fluoro, andthe dissolution of the amphiphilic polymer coating can be monitored as afunction of time.

In an embodiment, the amphiphilic polymer or co-polymer is an ionicthermoplastic co-polymer or co-polymer. For example, the amphiphilicpolymer or co-polymer can be poly (methyl vinyl ether-alt-maleic acidmonobutyl ester) (available under the trade name Gantrez ES-425, fromInternational Specialty Products (ISP), Wayne, N.J.) or poly (methylvinyl ether-alt-maleic acid monoethyl ester) (available under the tradename Gantrez ES-225, from International Specialty Products (ISP), Wayne,N.J.).

In an embodiment, the amphiphilic polymer(s) or co-polymer(s) is fullyamphiphilic. HPC (non-iodinated), iodinated HPC, PVP (non-iodinated)iodinated PVP (povidone iodine), PEG (non-iodinated), iodinated PEG,poly (methyl vinyl ether-alt-maleic acid monobutyl ester), and poly(methyl vinyl ether-alt-maleic acid monoethyl ester) are soluble inlower alcohols without the use of any water, which provides for a lowsurface tension and rapid evaporation. As used herein, the term “loweralcohols” means an alcohol having 4 carbon atoms or less. They are alsofreely soluble in water resulting in rapid dissolution in vivo. In anembodiment, this is beneficial when it is desired that the therapeuticagent transfer take place within 90 to 300 seconds of inflation. Whenthe above amphiphilic polymers or co-polymers are dissolved insufficient ethanol, alone or in combination, they are also freelymiscible with acetone. In an embodiment, where the therapeutic agentincludes paclitaxel, this can be beneficial because paclitaxel is highlysoluble in a mixture of a lower alcohol (e.g. ethanol, 2-propanol,n-butanol) and warm acetone, and the solvent combination enables a highdrug loading.

In another embodiment, the amphiphilic polymer(s) or co-polymer(s) maynot be fully amphiphilic. For example, methyl cellulose andhydroxypropyl methylcellulose are not fully soluble in non-aqueoussolvent, however some grades are soluble in a solution which containsapproximately 10% water and 90% non-aqueous solvent. It is also expectedthat other suitable co-polymers such as N-vinylpyrrolidone with otherreactive double bond containing monomers such as styrene, acrylic acid,vinyl acetate or vinyl caprolactam may not be fully soluble innon-aqueous solvent, but may be soluble in solutions containing a ratioin the range of 100% to 80% non-aqueous solvent, and 0% to 20% aqueoussolvent.

In an embodiment, the amphiphilic polymer coating may optionally includea plasticizer in the polymer matrix. A plasticizer may be particularlyuseful to increase the ductility and prevent the coating from crackingor delaminating while bending or folding in the dry state. Suitableplasticizers include, but are not limited to, propylene glycol, triethylcitrate, glycerol, and dibutyl sebacate. In an embodiment, theamphiphilic polymer is PVP-based (iodinated or non-iodinated) and theplasticizer is present at 30% to 85% by weight of the PVP. In anembodiment, the amphiphilic polymer is HPC-based (iodinated ornon-iodinated) and the plasticizer is present at 5% to 15% by weight ofthe HPC. In an embodiment, the plasticizer may also be an at leastpartially amphiphilic polymer. For example, PEG having a molecularweight below 10 K Daltons is a suitable plasticizer. In an embodiment,the plasticizer is PEG 400.

In an embodiment, the amphiphilic polymer coating may optionally includea wax in the polymer matrix. A wax-like surface assists with the glidingquality of the amphiphilic polymer coating in relation with a body lumensurface and/or in relation with an optional protective sheath over theamphiphilic polymer coating. Suitable waxes include, but are not limitedto bees wax, carnauba wax, polypropylene glycol, polydimethyl siloxane(PDMS), and PDMS derivatives.

In an embodiment, the amphiphilic polymer coating may optionally includea small minority of hydrophobic polymer or co-polymer in the polymermatrix to slightly extend the lifetime of the coating in vivo orslightly retard the release rate of the therapeutic agent, while stillallowing rapid and uniform dissolution of the coating in vivo.

In an embodiment, a continuous aggregate polymer matrix of the coatingis uniformly dissolvable and removable from the outer surface of theexpandable structure in an aqueous solvent, and at least partiallydissolvable in a non-aqueous solvent. Such a coating may be suitable forapplication in touch and go procedures where the therapeutic agenttransfer takes place within, for example, 90 to 300 seconds. In anembodiment, the coating is dissolvable in bovine serum such that 90%, byvolume, of the coating is removed within 300 seconds of soaking inbovine serum at 37° C., and more preferably within 90 seconds. Forexample, such dissolution can be accomplished when utilizing iodinatedor non-iodinated PVP or HPC. In an embodiment, the coating isdissolvable in bovine serum such that 50%, by volume, of the coating isremoved within 180 seconds of soaking in bovine serum at 37° C. Forexample, such an embodiment can be accomplished when utilizing iodinatedor non-iodinated PVP, HPC or PEG (MW 1.5 KD to 50 KD). It is expectedthat other iodinated or non-iodinated polymers such as methyl cellulose,hydroxypropyl methylcellulose, and co-polymers of N-vinylpyrrolidonewith other reactive double bond containing monomers such as styrene,acrylic acid, vinyl acetate or vinyl caprolactam, as well as poly(methyl vinyl ether-alt-maleic acid monobutyl ester), and poly (methylvinyl ether-alt-maleic acid monoethyl ester) should also exhibitsuitable solubility rates for application in touch and go procedureswhere the therapeutic agent transfer takes place within, for example, 90to 300 seconds.

Therapeutic Agents

In another aspect, embodiments of the invention disclose an apparatusand method for delivering therapeutic agents to treat a variety ofdiseases that arise in body lumen walls. The therapeutic agents usefulin accordance with the present invention may be used singly or incombination. The therapeutic agents may be non-aqueous soluble (i.e.solvent soluble) and/or aqueous soluble. In an embodiment, the driedcoating has a therapeutic agent (drug) to polymer matrix weight ratio(D/P) from 25-100%. As used herein the D in the D/P ratio includes allof the drugs in the coating unless the D/P ratio is utilized differentlyto specifically represent a single drug in the coating. As used hereinthe P in the D/P ratio includes all of the amphiphilic polymer and/orco-polymer(s), and additional components such as plasticizer and waxdispersed or otherwise uniformly integrated into the polymer matrix. TheD/P may depend upon the molecular weight of the amphiphilic polymerand/or co-polymer, and presence of additional components such as aplasticizer and/or wax. D/P ratios higher than 100% may result longerdissolution times in vivo, thereby providing less efficient drugdelivery during a treatment operation where a delivery balloon isinflated for 300 seconds or less. Additionally, D/P ratios higher than100% may increase the likelihood of particulate generation, particularlyfor water-insoluble drugs. D/P ratios below 25% may require excessivecoating thickness to achieve the required therapeutic agent loading onthe medical disposable device. In an embodiment, the D/P ratio is35-60%.

In an embodiment, the dried coating has a therapeutic agent (drug)density of approximately 0.1-10.0 μg/mm². The drug density may varydepending upon factors such as the specific drug and polymer matrixselections. In an embodiment, the dried coating is present on a catheterballoon, the drug is paclitaxel, and the amphiphilic polymer is PVP, andthe dried coating has a paclitaxel density of approximately 0.1-3.0μg/mm².

In an embodiment, non-aqueous soluble and/or water-insoluble therapeuticagents are particularly useful as components in a coating compositionwhich includes a majority or exclusively non-aqueous solvents. Forexample, a non-aqueous soluble anti-proliferative agent such aspaclitaxel may be used in combination with another therapeutic agentsuch as the anti-inflammatory agent dexamethasone. In an embodiment,therapeutic agents which may be, singly or in combination, locallydelivered to the surface of normal or diseased body lumens can beclassified into the categories of anti-proliferative agents,anti-platelet agents, anti-inflammatory agents, anti-thrombotic agents,and thrombolytic agents. These classes can be further sub-divided. Forexample, anti-proliferative agents can be anti-mitotic. Anti-mitoticagents inhibit or affect cell division, whereby processes normallyinvolved in cell division do not take place. One sub-class ofanti-mitotic agents includes vinca alkaloids. Representative examples ofnon-aqueous soluble vinca alkaloids include, but are not limited to,paclitaxel (including the alkaloid itself and naturally occurring formsand derivatives thereof, as well as synthetic and semi-synthetic formsthereof), vincristine, etoposide, indirubin, and anthracyclinederivatives, such as, for example, daunorubicin, daunomycin, andplicamycin. Other sub-classes of anti-mitotic agents includeanti-mitotic alkylating agents, such as, for example non-aqueous solublefotemustine, and anti-mitotic metabolites, such as, for example,non-aqueous soluble azathioprine, mycophenolic acid, leflunomide,teriflunomide, fluorouracil, and cytarabine. Anti-mitotic alkylatingagents affect cell division by covalently modifying DNA, RNA, orproteins, thereby inhibiting DNA replication, RNA transcription, RNAtranslation, protein synthesis, or combinations of the foregoing.

Examples of non-aqueous soluble anti-inflammatory agents that can alsobe used include, but are not limited to, dexamethasone, prednisone,hydrocortisone, estradiol, triamcinolone, mometasone, fluticasone,clobetasol, and non-steroidal anti-inflammatories, such as, for example,acetaminophen, ibuprofen, and sulindac. The arachidonate metaboliteprostacyclin or prostacyclin analogs are examples of a vasoactiveantiproliferative.

Therapeutic agents with pleiotropic effects on cell proliferation,immunomodulation and inflammation may also be used. Examples of suchnon-aqueous soluble agents include, but are not limited to themacrolides and derivatives thereof such as sirolimus (e.g. rapamycin),tacrolimus, everolimus, temsirolimus.

Anti-platelet agents are therapeutic entities that act by (1) inhibitingadhesion of platelets to a surface, typically a thrombogenic surface,(2) inhibiting aggregation of platelets, (3) inhibiting activation ofplatelets, or (4) combinations of the foregoing. Non-aqueous solubleanti-platelet agents that act as inhibitors of adhesion of plateletsinclude, but are not limited to, and tirofiban and RGD(Arg-Gly-Asp)-based peptides (Pegylated) that inhibit binding togpIIbIIIa or .alpha.v.beta.3, compounds that block P-selectin orE-selectin binding to their respective ligands. Agents that inhibitADP-mediated platelet aggregation include, but are not limited to,cilostazol.

Anti-thrombotic agents include chemical and biological entities that canintervene at any stage in the coagulation pathway. Examples of specificnon-aqueous soluble entities include, but are not limited to, smallmolecules that inhibit the activity of factor Xa. Also included aredirect thrombin inhibitors, such as, for example, argatroban, inogatran.

Other non-aqueous soluble therapeutic agents that can be used arecytotoxic drugs, such as, for example, apoptosis inducers, andtopoisomerase inhibitors, including, irinotecan, and doxorubicin, anddrugs that modulate cell differentiation such as inhibitors of histonedeacetylase, including valproic acid.

Other non-aqueous soluble therapeutic agents that can be used includeanti-lipaedemic agents, including but not limited to fenofibrate,clofibrate, and rosiglitazone and matrix metalloproteinase inhibitors,such as, for example, batimistat, antagonists of the endothelin-Areceptor, such as, for example, darusentan.

In another embodiment, aqueous soluble therapeutic agents may be used.Aqueous soluble anti-mitotic agents include Epothilone A, Epothilone Band Epothilone D, and all other Epothilones. Aqueous solubleanti-platelet agents include RGD (Arg-Gly-Asp)-based peptides thatinhibit binding to gpIIbIIIa or .alpha.v.beta.3. Aqueous solubleanti-thrombotic agents include heparinoid-type agents that can inhibitboth FXa and thrombin, either directly or indirectly, such as, forexample, heparin, heparin sulfate, low molecular weight heparins, suchas, for example, the compound having the trademark Clivarin®, andsynthetic oligosaccharides, such as, for example, the compound havingthe trademark Arixtra®. Aqueous soluble thrombolytic agents, which maybe defined as agents that help degrade thrombi (clots), can also be usedas adjunctive agents, because the action of lysing a clot helps todisperse platelets trapped within the fibrin matrix of a thrombus.Representative examples of thrombolytic agents include, but are notlimited to, urokinase or recombinant urokinase, pro-urokinase orrecombinant pro-urokinase, tissue plasminogen activator or itsrecombinant form, and streptokinase. Additional aqueous solubletherapeutic agents include recombinant antibodies for anti-platelet andanti-endothelin applications.

When used in the above or other treatments, a therapeutically effectiveamount of one of the non-aqueous soluble or aqueous soluble therapeuticagents in embodiments of the invention may be employed in pure form or,where such forms exist, in pharmaceutically acceptable salt, ester orprodrug form. Alternatively, the therapeutic agent may be administeredas a pharmaceutical composition including the compound of interest incombination with one or more pharmaceutically acceptable excipients. Asused herein, the phrase “therapeutically effective amount” of thetherapeutic agents of the invention means a sufficient amount of thetherapeutic agents to treat disorders, at a reasonable benefit/riskratio applicable to any medical treatment. It will be understood,however, that the total daily usage of the therapeutic agents andcompositions of embodiments of the invention will be decided by theattending physician within the scope of sound medical judgment. Thespecific therapeutically effective dose level for any particular patientwill depend upon a variety of factors including the disorder beingtreated and the severity of the disorder; activity of the specificcompound employed; the specific composition employed; the age, bodyweight, general health, sex and diet of the patient; the time ofadministration, route of administration, and rate of excretion of thespecific compound employed; the duration of the treatment; drugs used incombination or coincidental with the specific compound employed; andlike factors well known in the medical arts. For example, it is wellwithin the skill of the art to start doses of the therapeutic agent atlevels lower than required to achieve the desired therapeutic effect andto gradually increase the dosage until the desired effect is achieved.

Coating Process

The amphiphilic polymer coating containing a therapeutic agent or agentsand an amphiphilic polymer or co-polymer can be formed from with avariety of techniques including deposition, spray coating, and dipcoating. FIG. 1A-FIG. 1C are illustrations of a particular embodiment inwhich the amphiphilic polymer coating is formed by dip coating theexpandable structure of a medical disposable device, such as the balloonof a balloon catheter, into a coating solution or coating mixture.Utilizing embodiments of the invention, the dip coating process canprovide a uniform therapeutic agent density across the balloon surfaceusing a simple and reproducible single-dip, thereby eliminating the needfor multiple dips to load the therapeutic agent into the coating.

FIG. 1A is an illustration of a balloon catheter 110 with an uncoatedballoon 112 in the expanded position (e.g. inflated). As shown in FIG.1B, the uncoated expanded balloon 112 can be dipped into a coatingsolution or mixture 114 and then extracted from coating solution 114 ata rate of 0.05 to 0.4 in/min. As described above, the coating solution114 may include aqueous or more preferably non-aqueous solvents, anamphiphilic polymer or co-polymer, and a therapeutic agent. The coatingsolution 114 may optionally include additional components such as aplasticizer and/or wax.

In an embodiment, the coating solution 114 viscosity is at least 5 cpsand less than approximately 75 cps. After dipping the expanded balloon112 into the coating solution 114, the expanded balloon 112 is thenremoved from the coating solution, as shown in FIG. 1C resulting in auniform coating 116 on the expanded balloon 112. In an embodiment,optionally a gas (e.g. argon, oxygen) plasma may be used on the catheterprior to coating to enhance the coating adhesion.

In an embodiment, the use of an amphiphilic polymer or co-polymer andnon-aqueous soluble therapeutic agent enables the use of non-aqueoussolvents to dissolve the polymer or co-polymer and therapeutic agent. Inalternate embodiments, where the therapeutic agent and/or amphiphilicpolymer or co-polymer is not fully soluble in non-aqueous solutions, anaqueous solution or a solution including a mixture of aqueous andnon-aqueous solvents may be used. A majority or exclusively non-aqueoussolvents in the coating solution provides rapid evaporation, a lowersurface tension, and improved substrate wetting compared to an aqueoussolution, which aids in obtaining coating uniformity. In an embodiment,a suitable solution may contain a ratio in the range of 100% to 80%non-aqueous solvent, and 0% to 20% aqueous solvent. For example,solvents with boiling points lower than water can be used singly or incombination in the coating solution 114, such as ethanol, methanol, ormethyl ethyl ketone, isopropanol (2-propanol), and/or butanol thatrapidly evaporate in ambient conditions, which consequently reducesgravity induced surface defects such as sagging. Dip coating into acoating solution with majority or exclusively non-aqueous solventspermits forming a coating with high levels of a therapeutic agent, andpermits forming a coating that provides a uniform therapeutic agentdensity across the balloon surface using a simple, reproducible andhence easily manufacturable application process. For example, when HPC(non-iodinated), iodinated HPC, PVP (non-iodinated), iodinated PVP(povidone iodine), PEG (non-iodinated), iodinated PEG, poly (methylvinyl ether-alt-maleic acid monobutyl ester), and poly (methyl vinylether-alt-maleic acid monoethyl ester) are dissolved in sufficientethanol, they are also freely miscible with acetone. In an embodiment,where the therapeutic agent includes paclitaxel, this can be beneficialbecause paclitaxel is highly soluble in a mixture of a lower alcohol(e.g. ethanol, 2-propanol, n-butanol) and acetone, and the solventcombination enables a high drug loading. In an embodiment, thetherapeutic agent is rapamycin or everolimus. In an embodiment includingmethyl cellulose, hydroxypropyl methylcellulose, and/or co-polymers ofN-vinylpyrrolidone with other reactive double bond containing monomerssuch as styrene, acrylic acid, vinyl acetate or vinyl caprolactam, thesolution may contain water up to a ratio of 80/20 non-aqueous to aqueoussolvents.

The coating solution 114 may be prepared by mixing the therapeuticagent, solvent(s), polymer(s) and other components such as plasticizerinto a single container. Several mixing and/or dissolving operations maybe also performed prior to combining multiple solutions to form thecoating solution 114. For example, where an amphiphilic polymer orco-polymer is complexed with iodine, a complexed polymer solution may beprepared. For example, I₂ may be dissolved in alcohol (or a solutionhaving a ratio of up to 80/20 non-aqueous and aqueous solvents), thendry polymer powder is added to the I₂ and alcohol. Agitation and/or heatmay be applied to the solution to dissolve the polymer. For example,0.05 grams of I₂ is dissolved in 12 grams of 2-propanol. Then 1.00 gramsof PVP (360 KD, ISP) is added. The suspension is shaken continuouslyuntil the PVP is dissolved, about 1 hour. In an embodiment, theresulting solution is a 20% povidone-iodine in 2-propanol solution.

The therapeutic agent can then be dissolved in a separate alcohol,alcohol and acetone solution, or a solution having a ratio of up to80/20 non-aqueous and aqueous solvents. For example, 0.1 gramspaclitaxel is dissolved in 0.1 grams ethanol and 0.18 grams of 50%PEG-400 in acetone at 40° C. This solution can then be cooled to roomtemperature and added to 0.55 grams of the 20% povidone-iodine in2-propanol solution. In an embodiment, the combined coating solution hasa drug (i.e. paclitaxel) to polymer matrix (i.e. iodinated-PVP andPEG-400) ratio (D/P) of 50%, the solution is 31.8% non-volatile, and thedrug (i.e. paclitaxel) is 33% of the non-volatile. After coating, theballoon is dried, deflated and folded for delivery. In an embodiment,after the balloon is dried, but before deflating and folding fordelivery, the balloon may optionally be dip coated into a separatecoating solution containing a wax to form a thin wax coating (not shown)over the amphiphilic polymer coating, rather than incorporating the waxinto the amphiphilic polymer coating.

Local Therapeutic Agent Delivery Process

FIG. 2A-FIG. 2C are illustrations of a particular embodiment in whichthe amphiphilic polymer coating comprising a therapeutic agent andamphiphilic polymer or co-polymer is locally delivered to the surface ofa body lumen. As shown in FIG. 2A a balloon catheter 210 having anamphiphilic polymer coating 216 disposed on an unexpanded balloon 212 isprovided and inserted into a body lumen 220. The catheter 210 mayadditionally include an optional protective sheath 218 over theunexpanded balloon 212 to prevent the amphiphilic polymer coating 216from prematurely dissolving when the catheter is inserted into the bodylumen 220. In an embodiment, the body lumen 220 may be an arteryincluding a focal area 222, such as an unperturbed primaryatheroscolerotic or restenotic lesion. In an embodiment, the body lumen220 may be a common bile duct or a branch of a common bile duct andfocal area 222 is an intraluminal tumor.

As shown in FIG. 2B, the unexpanded balloon 212 is positioned adjacentthe focal area 222 and the protective sheath 218 is retracted. Theballoon 212 is then expanded (by inflation or otherwise) to contact theamphiphilic polymer coating 216 on the expanded balloon 212 against thebody lumen 220 where the focal area 222 exists. In an embodiment, theexpanded balloon 212 is a balloon catheter and the balloon is expandedto 2-20 atmospheres. Being amphiphilic, the coating 216 dissolvesimmediately when exposed to aqueous fluids such as blood in vivo. In anembodiment, at least 50%, by volume, of the amphiphilic polymer coatingis removed from the balloon within 180 seconds of inflating in vivo. Inan embodiment, at least 90%, by volume, of the amphiphilic polymercoating 216 is removed from the balloon within 300 seconds of inflating.In an embodiment, at least 90%, by volume, of the amphiphilic polymercoating 216 is removed from the balloon within 90 seconds of inflatingin vivo.

In clinical use for angioplasty, it may be preferable for the balloon212 to be expanded for only 5 to 300 seconds in a touch and goprocedure. This time limitation is due to the type of medical procedurebecause a longer use time with the balloon inflated could result infocal or adjacent tissue damage that is deleterious to the therapeuticintent of the procedure. This damage could result from mechanicalpressure and/or metabolic insufficiency caused by sustained inflation ofthe balloon including but not limited to tissue architecture, tissueinflammation, cell death, and induction of reactive scarring within theorgan. In an embodiment, a coated angioplasty balloon may be tracked toa target lesion using standard techniques, the optional protectivesheath is retracted and the angioplasty balloon is inflated against anartery wall. Hydration of the coating occurs immediately and causes thetherapeutic agent to release into tissue, the coating polymer orco-polymer to dissolve, and some of the amphiphilic polymer coating totransfer from the balloon to the artery wall. This paving acts as drugreservoir and is transient. The significant or total solubility of thepolymer or co-polymer in blood prevents embolic hazards associated withthe coating. Also, this active dissolution of the polymer or co-polymermatrix assists the transfer of hydrophobic and substantiallywater-insoluble therapeutic agents such as paclitaxel from the balloonto the tissue. In accordance with embodiments of the invention, asignificant portion of the therapeutic agent contained in the coatingmay be transferred to the tissue of the surrounding lumen during theprocedure. In an embodiment, at least 5% of the therapeutic agentcontained in the coating is imparted into the tissue of a vascular lumenwithin one hour of the touch and go procedure. In an embodiment, atleast 25% of the therapeutic agent contained in the coating is impartedinto the tissue of a vascular lumen within one hour of the touch and goprocedure.

Several embodiments of the invention are described below with referenceto the following non-limiting Examples regarding coating of PET coupons.Solution percentages provided are by weight.

Example 1

One (1.0) grams of a 7.5% solution of 60 K Dalton HPC in ethanol ismixed with 0.15 grams of 1% solution of propylene glycol (plasticizer)in acetone, 0.075 grams paclitaxel and 0.08 grams n-butanol. The mixtureis heated in a water bath to dissolve the paclitaxel; a clear solutionresults. When dip coated (single dip) on PET coupons at a dip speed ofabout 10 inches/minute, and dried at room temperature, there results aslightly milky dry coating. About 3 cm² of coupon surface is coated percoupon. The average coating density determined by gravimetric analysisis 6 μg/mm² and the implied paclitaxel density is 3 μg/mm². The drycoating is sufficiently ductile to withstand a 180 degree bend withoutcracking or delaminating.

A coupon coated as above is immersed in 3 ml of 37° C. water for 3minutes with agitation, after which the coupon is removed and the turbidsuspension diluted with 9 ml dimethyl sulfoxide (DMSO) to produce aclear solution. Quantitative UV analysis at 260 nm and 280 nm vs. astandard curve shows an 88% recovery. This result demonstrates the rapiddissolution of the amphiphilic polymer coating and drug release invitro. The in vivo milieu is expected to present serum proteins with asurfactant effect, which will increase the dissolution rate of the drugand coating polymer in vivo.

Example 2

0.075 grams paclitaxel is mixed with 0.9 grams of a 20% povidone-iodinesolution in 2-propanol, 0.06 grams of a 10% propylene glycol solution in2-propanol and 0.04 grams acetone. When dip coated (single dip) on a PETcoupon at a dip speed of 10 inches/min, and dried at room temperature,there results a clear amber dry coating. About 2.5 μg/mm² of paclitaxelis deposited.

The above coupon is immersed in 1.5 ml of 37° C. water for 30 seconds.All of the coating dissolves in the water, and the solution is totallytransparent amber, and not turbid as in Example 1.

Example 3

An identical formula to Example 2 is made, however non-iodinated PVP isemployed instead of povidone-iodine of the same molecular weight (40 KDalton). When dip coated (single dip) on a PET coupon at a dip speed of10 inches/min, and dried at room temperature, there results a clearwater white dry coating. About 2.5 μg/mm² of paclitaxel is deposited.

This coupon is immersed in 1.5 ml of 37° C. water for 30 seconds. All ofthe coating polymer dissolves in the water, and the solution shows asuspension of needle crystals. This suspension becomes more turbid after24 hours, while the above amber solution from Example 2 remainstransparent. This demonstrates that the povidone-iodine changes theaqueous solubility of paclitaxel.

Example 4

0.1 grams rapamycin (available from LC Laboratories, Woburn, Mass.) isdissolved in 0.08 grams of a 10% propylene glycol solution in 2-propanoland 0.053 grams acetone at 40° C. The solution is cooled to roomtemperature, then added to 1.2 grams of a 20% solution ofpovidone-iodine in 2-propanol. The formula is dip coated (single dip) ona Nylon 12 coupon, and dried at room temperature for 30 minutes. Theabove coupon is immersed in 1 ml of 37° C. water for one minute. All ofthe coating dissolves in the water, and the solution is clear amber.

Example 5

An identical formula to Example 4 is made, however non-iodinated C-30PVP is employed instead of povidone-iodine. The formula is dip coated(single dip) on a Nylon 12 coupon, and dried at room temperature for 30minutes. The above coupon is immersed in 1 ml of 37° C. water for oneminute. All of the coating dissolves in the water, and the solution isturbid due to the water-insoluble rapamycin.

Example 6

0.1 grams everolimus (available from LC Laboratories, Woburn, Mass.) isdissolved in 0.08 grams of a 10% propylene glycol solution in 2-propanoland 0.053 grams acetone at 40° C. The solution is cooled to roomtemperature, then added to 1.2 grams of a 20% solution ofpovidone-iodine in 2-propanol. The formula is dip coated (single dip) ona Nylon 12 coupon, and dried at room temperature for 30 minutes. Theabove coupon is immersed in 1 ml of 37° C. water for one minute. All ofthe coating dissolves in the water, and the solution is clear amber.

Example 7

An identical formula to Example 6 is made, however non-iodinated C-30PVP is employed instead of povidone-iodine. The formula is dip coated(single dip) on a Nylon 12 coupon, and dried at room temperature for 30minutes. The above coupon is immersed in 1 ml of 37° C. water for oneminute. All of the coating dissolves in the water, and the solution isturbid due to the water-insoluble everolimus.

Light scattering experiments at 600 nm and 700 nm were performedcomparing the drug (paclitaxel, rapamycin and eyerolimus) and polymereluted water solutions of Examples 2, 4 and 6 (containingpovidone-iodine) with Examples 3, 5 and 7 (containing non-iodinatedPVP). The results shown in Table I below provide a quite unexpectedincrease in solubility of paclitaxel, rapamycin and everolimus in thepovidone-iodine eluted water solutions of Examples 2, 4 and 6 comparedto the non-iodinated PVP eluted water solution of Examples 3, 5 and 7.Consequently, and quite unexpectedly this suggests that the iodinecomplexed PVP polymer may assist in tissue uptake of the non-aqueoussoluble therapeutic agents in vivo.

TABLE I Optical density measurements Thera- Ex- peutic Wave- OpticalSolubility ample Agent length Polymer Density Increase 2 paclitaxel 600nm PVP-iodinated 0.120 2.99 3 paclitaxel 600 nm PVP (non-iodinated)0.359 — 4 rapamycin 600 nm PVP-iodinated 0.079 3.10 5 rapamycin 600 nmPVP (non-iodinated) 0.245 — 6 everolimus 600 nm PVP-iodinated 0.068 2.387 everolimus 600 nm PVP (non-iodinated) 0.162 — 2 paclitaxel 700 nmPVP-iodinated 0.089 3.19 3 paclitaxel 700 nm PVP (non-iodinated) 0.284 —4 rapamycin 700 nm PVP-iodinated 0.056 3.66 5 rapamycin 700 nm PVP(non-iodinated) 0.205 — 6 everolimus 700 nm PVP-iodinated 0.051 2.66 7everolimus 700 nm PVP (non-iodinated) 0.136 —

Several embodiments of the invention are described below with referenceto the following non-limiting Examples regarding coating of Nylon 12coupons. Solution percentages provided are by weight.

Example 8

0.2 grams of iodine (Sigma-Aldrich) was added to 10 grams of methanoland dissolved with heat and agitation. 4.29 grams of PEG (4 K Daltons,Fluka) was then added, and dissolved with mild heat and agitation. 0.20grams of paclitaxel was added to 1.66 grams of the above PEG-iodinesolution. Mild heat and agitation were used to dissolve the paclitaxel.

A Nylon 12 coupon was coated with the formulation and dried for about 1hour. The coupon was then soaked in 1.5 ml bovine serum at 37° C. for 3minutes. 200 micro-liters of the serum sample was tested for opticaldensity at 600 and 700 nm on a plate reader.

Example 9

An identical formula to Example 8 is made without iodine as a counterexample. A Nylon 12 coupon was coated with the formulation and dried forabout 1 hour. The coupon was then soaked in 1.5 ml bovine serum at 37°C. for 3 minutes. 200 micro-liters of the serum sample was tested foroptical density at 600 and 700 nm on a plate reader.

Light scattering experiments at 600 nm and 700 nm were performedcomparing the drug (paclitaxel) and polymer eluted bovine serumsolutions of Example 8 (iodinated PEG) with Example 9 (non-iodinatedPEG). The results shown in Table II below provide a quite unexpectedincrease in solubility of paclitaxel in the PEG eluted bovine serumsolution of Example 8 compared to the non-iodinated PEG eluted bovineserum solution of Example 9. Consequently, and quite unexpectedly thissuggests that the iodine complexed PEG polymer may assist in tissueuptake of the non-aqueous soluble therapeutic agents in vivo.

TABLE II Optical density measurements Therapeutic Optical SolubilityExample Agent Wavelength Polymer Density Increase Serum — 600 nm — 0.099— blank 8 paclitaxel 600 nm PEG-4KD- 0.109 1.13 iodinated 9 paclitaxel600 nm PEG-4KD- 0.123 — (non-iodinated) Serum — 700 nm — 0.062 — blank 8paclitaxel 700 nm PEG-4KD- 0.069 1.26 iodinated 9 paclitaxel 700 nmPEG-4KD- 0.087 — (non-iodinated)Clinical Study 1

0.1 grams paclitaxel was dissolved in 0.1 grams ethanol and 0.18 gramsof 50% PEG-400 in acetone at 45° C. The solution was then cooled to roomtemperature and added to 0.55 grams of 20% povidone-iodine in2-propanol. The resulting coating solution contained a D/P ratio of 50%,31.8 wt % non-volatile components, with the paclitaxel representing 33.3wt % of the non-volatile components.

Two 2.0×20 over-the-wire balloon catheters (available from ev3 Inc.,Plymouth, Minn.) were inflated and cleaned by sonication in 2-propanolfor 30 seconds. The catheters were then dried at room temperature andplasma treated for 18 seconds in an argon atmosphere while the balloonswere rotated at 0.17 in/min. The balloons were dipped into the resultingcoating solution and extracted at a 30 degree angle from horizontal,while rotating the balloon at 30 rpm. When dried, the amount of driedcoatings on the balloons was about 1.1-1.2 mg. The first balloon wasextracted at 0.17 in/min, resulting in an approximate paclitaxel densityof 2.8 μg/mm² on the balloon surface when dried. The second balloon wasextracted at 0.15 in/min, resulting in a drug density of 2.4 μg/mm² onthe balloon surface when dried. Efficacy of the paclitaxel tissue uptakewas tested in vivo in three New Zealand white rabbits. Carotid andfemoral arteries were exposed via cut downs, and the catheters wereinserted directly into the artery segments, inflated to nominal diameterfor 60 seconds, then deflated and removed. The treated artery segmentswere removed at 40 minutes post deflation and stored immediately on dryice. Subsequent analysis by liquid chromatography-mass spectrometry(LC/MS) for paclitaxel showed that the average drug concentration in thetissue for the first balloon was 500 paclitaxel/gram tissue, and 381 μgpaclitaxel/gram tissue for the second balloon.

Clinical Study 2

An iodinated-PEG solution with paclitaxel was prepared as described inExample 8, except that the molecular weight of PEG used was 10 K Daltons(Fluka). Three 2.5×20 over-the-wire balloon catheters (ev3, Inc.) wereinflated and cleaned by sonication in 2-propanol for 30 seconds. Thecatheters were dried at room temperature and subsequently plasma treatedfor 18 seconds in an atmospheric argon plasma while the balloons wererotated at 30 rpm in the plasma jet. The balloons were then dipped intothe coating solution and extracted. When dried, the amount of driedcoating on the balloons was about 1.8 mg to 1.9 mg, approximating a drugdensity of 3 μg/mm² on the balloon surface. The dried catheters weresheathed.

Efficacy of the paclitaxel tissue uptake was texted in vivo in three NewZealand white rabbits. Carotid and femoral arteries were exposed via cutdowns, and the catheters were inserted directly into the arterysegments, inflated to nominal diameter for 60 seconds, then deflated andremoved. The treated artery segments were removed at 40 minutes postdeflation and stored immediately on dry ice. Subsequent analysis byLC/MS for paclitaxel showed that the average drug concentration intissue was 867 μg/g (μ gram drug/gram tissue).

In both clinical studies the amount of average paclitaxel uptake by thetissue was greater than data provided in the SeQuent® Please productbrochure number 6050120 (available from B. Braun Vascular Systems,Berlin, Germany) where a tissue concentration of approximately 325 μgpaclitaxel/gram tissue was reported in porcine coronary arteries atroughly the same time period (approximately 40 minutes) post deflationin which a paclitaxel drug loading of 3 μg/mm² in a polymer-free coatingwas utilized.

Diseases of the Vasculature

One therapeutic area where embodiments of the present invention will beapplicable is the treatment of luminal disorders of the vasculature. Ingeneral, luminal disorders may be classified as native (atherosclerotic,thromboembolic) or iatrogenic (restenosis) diseases. These luminaldisorders may include but not be limited to atherosclerosis,atheromatous lesions, vulnerable plaque, thromboembolic obstructions,vascular graft disease, arteriovenous fistula disease, arteriovenousgraft disease and restenosis.

Atherosclerosis is a complex disease of the vessel wall involving theinterplay of inflammation, proliferation, lipid deposition and thrombusformation. Atherosclerosis promotes the formation of atheromatousplaques that may progress slowly over several years, leading toprogressive obstruction of the vessel lumen manifesting clinically asangina. Atheromatous plaques, may also become “vulnerable plaques” dueto an unstable collection of white blood cells (primarily macrophages)and lipids (including cholesterol) in the wall of an artery and becomeparticularly prone to rupture. A rupture of a vulnerable plaque iscommonly believed to be the cause of sudden thrombotic obstructions ofthe vessel lumen due to the rapid formation of blood clots at therupture site, leading to the clinical manifestations of heart attack orstroke. Vulnerable plaques may not significantly obstruct a vessel lumenuntil rupture, thus they are pre-obstructive lesions. It is envisionedthat a desirable therapeutic target is the prevention of obstruction ofthe vessel lumen by the treatment of vulnerable plaques prior to theirrupture. Specifically, embodiments of the present invention could beapplied to a catheter with a tip that is expandable to allow uniform andcomplete contact with and delivery of therapeutic agents to sites ofluminal atheromatous or vulnerable plaques. The local delivery oftherapeutic agents would enable a much higher, targeted, localconcentration of said agents than might otherwise be achieved bysystemic delivery. Moreover, a local delivery strategy would enable theuse of therapeutic agents that otherwise may be poor candidates forsystemic delivery due to lack of bioavailability and/or undesirable ortoxic side effects at concentrations needed to achieve efficacy.

Restenosis

One therapeutic area where embodiments of the present invention will beapplicable is inhibiting the process of restenosis. Restenosis is theresult of a complex process involving inflammation and proliferationactivated by a response to a percutaneous or surgical vascularintervention. Examples of these percutaneous or surgical interventionsmay include but are not limited to the revascularization of vascularbypass grafts, arteriovenous fistulas, arteriovenous grafts andpercutaneous revascularization of coronary, femoral, and carotidvessels. Atherosclerotic plaque arising from the arterial wall canreduce cross-sectional flow area which limits flow to downstream organs.Cross-sectional flow area can be restored by displacing (e.g. expandableballoon or stent) or removing the lesion (e.g. directional or rotationalatherectomy). In the months to weeks after revascularization localproliferative of arterial wall smooth muscle cells can create anobstruction to flow at the site of the original atherosclerotic plaque.Paclitaxel is a diterpene molecule containing a complex taxane ring thatinhibits cytokinesis by promoting microtubule polymerization. Paclitaxelinhibits smooth muscle cell proliferation and restenosis after balloonangioplasty in a mammalian arteries. Paclitaxel inhibits restenosisafter percutaneous coronary revascularization in humans when it isdelivered over days to weeks from implanted metal stents that wereretained after the revascularization procedure. Brief exposure topaclitaxel (20 minutes of less) can inhibit smooth muscle cellproliferation for sustained periods (14 days). Clinical studiesdemonstrate that paclitaxel can also effectively inhibit restenosisafter femoral and coronary revascularization when it is delivered over ashort period (minutes) from an expandable balloon coated with the drug.

Restenosis is a complex molecular process that involves both smoothmuscle cell proliferation in addition to inflammatory processes.Dexamethasone is a glucocorticoid that reduces inflammation andrestenosis after balloon angioplasty in a mammalian arteries. Thissuggests that there may be clinical benefit in delivering antimitoticagents such as paclitaxel in combination with anti-inflammatory agentssuch as dexamethasone from an expandable balloon coated with the twotherapeutic agents.

Pulmonary Disease

Another therapeutic area where embodiments of the present inventioncould be applicable is a luminal surface of normal or diseased airwayfor the treatment or prevention of focal diseases of the lung andairways. This embodiment may be used in conjunction with both a rigid orflexible bronchoscope which are commonly used to facilitate access toand visualization of the target treatment area.

In general, focal diseases of the airways area neoplasms that arecategorized as either benign or malignant. Primary neoplasms may beclassified as epithelial, mesenchymal or lymphoid tumors; more than 20types of tracheal neoplasms have been described.

Carcinoid tumors represent approximately 85 percent of adenomas of thetracheobronchial tree. Adenoid cystic carcinoma is the most frequentadenoma of the trachea. Adenoid cystic carcinoma (or cylindroma) is thesecond most common malignancy and also the second most common primarytracheal neoplasm.

Conventional treatment for lung cancer can involve surgical removal oftumor, chemotherapy, or radiation therapy, as well as combinations ofthese methods. The decision about which treatments will be appropriatetake into account the localization and extent of the tumor as well asthe overall health status of the patient. An example of adjuvant therapyis chemotherapy or radiotherapy administered after surgical removal of atumor in order to be certain that all tumor cells are killed.

Depending upon the specific neoplasm type and behavior as well as thetime of diagnosis, the neoplasm may or may not present a physicalobstruction or protrusion into the lumen of the airways. It isenvisioned that an approach to restoring functional luminal patencycould be to mechanically restore luminal patency by displacing the tumorwith a balloon or reduce tumor bulk and then locally delivering a drugto inhibit tumor growth and/or tumor survival. Local drug delivery usingembodiments of the present invention could be an effective method ofdelivering chemotherapeutic agents effective against benign or malignantneoplasms to the luminal aspect of the tumor. Specifically, embodimentsof the present invention could be applied to a catheter or abronchoscope and advanced antegradely or retrogradely to the intendedsite of local drug delivery. It is envisioned that embodiments of thepresent invention will enable the local delivery of bioactive(therapeutic) agents to the surface of normal or diseased airway lumensand may be used singly or in combination with surgical removal,chemotherapy and radiation therapy. The local delivery of therapeuticagents would enable a much higher, targeted, local concentration of saidagents than might otherwise be achieved by systemic delivery. Moreover,a local delivery strategy would enable the use of therapeutic agentsthat otherwise may be poor candidates for systemic delivery due to lackof bioavailability and/or undesirable or toxic side effects atconcentrations needed to achieve efficacy. The targeted local deliveryof therapeutic agents may be used to reduce tumor size to facilitatesurgical removal and may eliminate the need for and/or reduce theduration or intensity of systemic chemotherapy or radiotherapy whichhave numerous unpleasant side effects.

Gastrointestinal Disease

Another therapeutic area where embodiments of the present inventioncould be applicable is gastrointestinal disease including, but limitedto, benign and malignant tumors of the esophagus, biliary tract, colon,and small bowel.

Esophageal tumors are caused by dysregulated division of esophagealsmooth muscle or epithelial cells. The tumors can be either benign (e.g.leiomyoma) or malignant (squamous cell carcinoma or adenocarcinoma).These tumors can grow into the lumen and compromise the functionalcross-sectional area of the esophagus causing dysphagia (abnormalswallowing) and consequent malnutrition.

It is envisioned that an approach to restoring functional luminalpatency could be to mechanically restore luminal patency by displacingthe tumor with a balloon or metal dilator or reduce tumor bulk (e.g.laser ablation), and then locally delivering a therapeutic agent toinhibit tumor growth and/or tumor survival. Local therapeutic agentdelivery using embodiments of the present invention could be aneffective method of delivering chemotherapeutic agents effective againstbenign or malignant esophageal tumors to the luminal aspect of thetumor. Specifically, embodiments of the present invention could beapplied to a catheter or an endoscope and advanced antegradely orretrogradely to the intended site of local drug delivery.Chemotherapeutic agents that could be effective in this manner include,but are not limited to, microtubule stabilizing agents (e.g. taxanesincluding paclitaxel and epothilones), topoisomerase I inhibitors (e.g.irinotecan), platinum derivatives (e.g. oxaliplatin, cisplatin,carboplatin), anthracyclines (daunorubicin, epirubicin), 5-FU, andtargeted biologic therapies (e.g. anti-VEGF antibodies such asbevacizumab). The advantages of this method are that high doses ofeffective chemotherapeutic agents can be delivered to the tumor withoutsystemic toxicity, the patient's diet would not have to be modified toprevent food impaction, and the mechanical complications of stentplacement including indirect tracheal compression, stent migration, andstent occlusion could be avoided. Therapeutic agent for the aboveindication that exhibit water-only solubility or require water forsolubilization such as carboplatin, cisplatin, the epothilones, andtargeted proteins such as antibodies (such as the anti-VEGF antibodybevacizumab) can be formulated into the disclosed amphiphilic polymercoating by the use of water as part or all of the solvent.

A similar approach could be used with malignancies of the biliary tract.Cholangiocarcinoma is the most common biliary tract malignancy. It iscaused by dysregulated division of cholangiocytes. These tumors cancompromise the functional lumen of the intra- or extra-hepatic biliarytree causing cholestasis and consequent cholangitis, pruritis, fatmalabsorption, and anorexia.

It is envisioned that an approach to restoring functional luminalpatency could be to mechanically restore luminal patency by displacingthe tumor with a balloon, blade, or metal dilator or reduce tumor bulk(e.g. laser ablation), and then locally deliver a therapeutic agent toinhibit tumor growth and/or tumor survival utilizing embodiment of thepresent invention. Chemotherapeutic agents that could be effective inthis manner include, but are not limited to, microtubule stabilizingagents (e.g. taxanes including paclitaxel and epothilones), platinumderivatives (e.g. oxaliplatin, cisplatin, carboplatin), anthracyclines(daunorubicin, epirubicin), 5-FU, DNA cross-linkers (mitomycin-C),alkylating nitrosoureas (lomustine), interferons (interferon-alpha), andtargeted biologically active agents (e.g. EGFR inhibitors such ascetuximax). The advantages of this method are that high doses ofeffective chemotherapeutic agents can be delivered to the tumor withoutsystemic toxicity, and the mechanical complications of stent placementincluding stent migration and stent occlusion could be avoided.

Approaches similar to that described above for esophageal and biliarytract malignancies could be developed for small bowel and colonicmalignancies. Analogous approaches could also be used to locallydelivery therapeutic agents to non-malignant gastrointestinal diseases(e.g. anti-inflammatory agents delivered to treat inflammatory boweldisease). Therapeutic agents for the above indication that exhibitwater-only solubility or require water for solubilization such ascarboplatin, cisplatin, the epothilones, interferons (interferon-alpha)and targeted proteins such as antibodies (such as the EGFR inhibitorcetuximab) can be formulated into the disclosed amphiphilic polymercoating by the use of water as part or all of the solvent system.

In the foregoing specification, various embodiments of the inventionhave been described. It will, however, be evident that variousmodifications and changes may be made thereto without departing from thebroader spirit and scope of the invention as set forth in the appendedclaims. The specification and drawings are, accordingly, to be regardedin an illustrative sense rather than a restrictive sense.

What is claimed is:
 1. A method of delivering a substantiallywater-insoluble therapeutic agent to a vascular lumen comprising:providing a catheter assembly having a non-durable coating disposed onan outer surface of an expandable structure of the catheter assembly,wherein the non-durable polymer coating is complexed with iodine and hasa substantially water-insoluble therapeutic agent dispersed therein;introducing the catheter assembly into a vascular lumen; expanding theexpandable structure of the catheter assembly to contact the non-durablecoating against the vascular lumen; and contracting the expandablestructure.
 2. The method of claim 1, wherein the substantiallywater-insoluble therapeutic agent is selected from the group consistingof an anti-proliferative agent, anti-platelet agent, anti-inflammatoryagent, anti-thrombotic agent, and thrombolytic agent.
 3. The method ofclaim 2, wherein at least 50% of the non-durable coating is dissolvedwithin 180 seconds of the expanding.
 4. The method of claim 3, whereinat least 90% of the non-durable coating is dissolved within 300 secondsof the expanding.
 5. The method of claim 2, wherein the substantiallywater-insoluble therapeutic agent is paclitaxel.
 6. The method of claim5, wherein at least 5% of the therapeutic agent contained in thenon-durable coating is imparted into tissue of the vascular lumen withinone hour of contracting the expandable structure.
 7. The method of claim6, wherein at least 25% of the therapeutic agent contained in thenon-durable coating is imparted into tissue of the vascular lumen withinone hour of contracting the expandable structure.
 8. The method of claim1, wherein the iodine is complexed with a polymer selected from thegroup consisting of polyethylene glycol (PEG), polyvinyl pyrrolidone(PVP) and hydroxypropyl cellulose (HPC) in the non-durable coating. 9.The method of claim 1, wherein the iodine is complexed with a polymerselected from the group consisting of methyl cellulose and hydroxypropylmethylcellulose, or a co-polymer of N-vinylpyrrolidone with a reactivedouble bond containing monomer.
 10. A method of delivering asubstantially water-insoluble therapeutic agent to a vascular lumencomprising: providing a catheter assembly having a non-durable coatingdisposed on an outer surface of an expandable structure of the catheterassembly, wherein the non-durable coating comprises a substantiallywater-insoluble therapeutic agent dispersed amongst non-covalently boundiodine within a polymer matrix; introducing the catheter assembly into avascular lumen; expanding the expandable structure of the catheterassembly to contact the non-durable coating against the vascular lumen;and contracting the expandable structure.
 11. The method of claim 10,wherein the substantially water-insoluble therapeutic agent is selectedfrom the group consisting of an anti-proliferative agent, anti-plateletagent, anti-inflammatory agent, anti-thrombotic agent, and thrombolyticagent.
 12. The method of claim 11, wherein at least 50% of thenon-durable coating is dissolved within 180 seconds of the expanding.13. The method of claim 12, wherein at least 90% of the non-durablecoating is dissolved within 300 seconds of the expanding.
 14. The methodof claim 11, wherein the substantially water-insoluble therapeutic agentis paclitaxel.
 15. The method of claim 14, wherein at least 5% of thetherapeutic agent contained in the non-durable coating is imparted intotissue of the vascular lumen within one hour of contracting theexpandable structure.
 16. The method of claim 15, wherein at least 25%of the therapeutic agent contained in the non-durable coating isimparted into tissue of the vascular lumen within one hour ofcontracting the expandable structure.
 17. The method of claim 10,wherein the polymer matrix comprises a polymer selected from the groupconsisting of polyethylene glycol (PEG), polyvinyl pyrrolidone (PVP)hydroxypropyl cellulose (HPC), methyl cellulose and hydroxypropylmethylcellulose, or a co-polymer of N-vinylpyrrolidone with a reactivedouble bond containing monomer.
 18. The method of claim 10, whereinpaclitaxel is dispersed amongst non-covalently bound iodine within apolymer matrix comprising polyethylene glycol (PEG).
 19. The method ofclaim 10, further comprising withdrawing a protective sheath from overthe expandable structure prior to expanding the expandable structure.20. The method of claim 10, further comprising contacting thenon-durable coating against an atheroscolerotic or restenotic lesion.